225 research outputs found

    Maternal and fetal origins of cardiovascular disease: The Generation R Study

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    In de afgelopen twintig jaar zijn in epidemiologisch onderzoek associaties aangetoond tussen een laag geboortegewicht en de ontwikkeling van hart en vaatziekten en de risicofactoren daarvoor op latere leeftijd. De ‘foetale origine van volwassen aandoeningen’ hypothese veronderstelt dat een ongunstige foetale omgeving leidt tot aanpassingen in de ontwikkeling die permanent de structuur, fysiologie en het metabolisme van de foetus beïnvloeden. Dit leidt tot foetale groeivertraging en een laag geboortegewicht en zou ten gunste zijn voor de overleving op korte termijn. Lange termijn eff ecten zouden echter schadelijk zijn en leiden tot hart en vaatziekten. Door deze hypothese is recent de zoektocht naar de oorsprong van hart en vaatziekten uitgebreid van epidemiologisch onderzoek bij volwassenen en kinderen naar onderzoek gericht op het foetale en vroege postnatale leven. Hoewel het geboortegewicht makkelijk te meten is en beschikbaar is uit obstetrische dossiers, is het waarschijnlijk niet de beste afspiegeling van een ongunstige foetale omgeving of blootstelling. Hetzelfde geboortegewicht kan het resultaat zijn van verschillende foetale blootstellingen en groeipatronen. Roken van moeder tijdens de zwangerschap is de belangrijkste determinant van laag geboortegewicht in westerse landen. Een ongunstige foetale omgeving als gevolg van roken van moeder kan door de directe effecten van nicotine en de geassocieerde maternale levensstijl en voedingsgewoonten leiden tot veranderingen in de ontwikkeling. Om die reden zou roken van moeder tijdens de zwangerschap een betere afspiegeling kunnen zijn van een nadelige foetale omgeving dan het geboortegewicht. De ‘foetale origine van volwassen aandoeningen’ hypothese was de belangrijkste aanleiding tot het doen van het onderzoek dat beschreven wordt in dit proefschrift. Het doel van dit onderzoek was om mechanismen te identificeren die leiden van ongunstige foetale blootstellingen, tot suboptimale foetale groeipatronen en vervolgens tot de ontwikkeling van risicofactoren voor hart en vaatziekten. Hierbij hebben we ons gericht op roken van moeder tijdens de zwangerschap als ongunstige foetale blootstelling. Er zijn verschillende hypothesen voorgesteld voor mechanismen die de associaties tussen een laag geboortegewicht en ziekten op de volwassen leeftijd zouden kunnen verklaren. Deze hypothesen stellen een centrale rol voor voor 1) foetale ondervoeding; 2) toegenomen foetale blootstelling aan cortisol; 3) genetische aanleg voor zowel laag geboortegewicht als ziekten op de volwassen leeftijd; en 4) versnelde postnatale groei van kinderen met een laag geboortegewicht. In hoofdstuk 2 worden resultaten beschreven van eerder verricht epidemiologisch onderzoek, dat opgezet was om deze hypothesen te testen. Het is nog niet bekend welke mechanismen de associaties tussen laag geboortegewicht en ziekten op de volwassen leeftijd verklaren

    The Cardiovascular Stress Response as Early Life Marker of Cardiovascular Health: Applications in Population-Based Pediatric Studies—A Narrative Review

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    Stress inducement by physical exercise requires major cardiovascular adaptations in both adults and children to maintain an adequate perfusion of the body. As physical exercise causes a stress situation for the cardiovascular system, cardiovascular exercise stress tests are widely used in clinical practice to reveal subtle cardiovascular pathology in adult and childhood populatio

    Associations of maternal early-pregnancy blood glucose and insulin concentrations with DNA methylation in newborns

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    BACKGROUND: Intrauterine exposure to a disturbed maternal glucose metabolism is associated with adverse offspring outcomes. DNA methylation is a potential mechanism underlying these associations. We examined whether maternal early-pregnancy glucose and insulin concentrations are associated with newborn DNA methylation. In a population-based prospective cohort study among 935 pregnant women, maternal plasma concentrations of non-fasting glucose and insulin were measured at a median of 13.1 weeks of gestation (95% range 9.4-17.4). DNA methylation was measured using the Infinium HumanMethylation450 BeadChip (Ilumina). We analyzed associations of maternal early-pregnancy glucose and insulin concentrations with single-CpG DNA methylation using robust linear regression models. Differentially methylated regions were analyzed using the dmrff package in R. We stratified the analyses on normal weight versus overweight or obese women. We also performed a look-up of CpGs and differently methylated regions from previous studies to be associated with maternal gestational diabetes, hyperglycemia or hyperinsulinemia, or with type 2 diabetes in adults. RESULTS: Maternal early-pregnancy glucose and insulin concentrations were not associated with DNA methylation at single CpGs nor with differentially methylated regions in the total group. In analyses stratified on maternal BMI, maternal early-pregnancy glucose concentrations were associated with DNA methylation at one CpG (cg03617420, XKR6) among normal weight women and at another (cg12081946, IL17D) among overweight or obese women. No stratum-specific associations were found for maternal early-pregnancy insulin concentrations. The two CpGs were not associated with birth weight or childhood glycemic measures (p values > 0.1). Maternal early-pregnancy insulin concentrations were associated with one CpG known to be related to adult type 2 diabetes. Enrichment among nominally significant findings in our maternal early-pregnancy glucose concentrations was found for CpGs identified in a previous study on adult type 2 diabetes. CONCLUSIONS: Maternal early-pregnancy glucose concentrations, but not insulin concentrations, were associated with DNA methylation at one CpG each in the subgroups of normal weight and of overweight or obese women. No associations were present in the full group. The role of these CpGs in mechanisms underlying offspring health outcomes needs further study. Future studies should replicate our results in larger samples with early-pregnancy information on maternal fasting glucose metabolism

    Invloed van DNA-methylatie op gezondheid en ziekte van kinderen

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    De ontwikkeling in de eerste fase van het leven is van groot belang voor de gezondheid van kinderen en volwassenen. Ongunstige invloeden in specifieke kritieke perioden tijdens de vroege ontwikkeling hebben nadelige effecten op de gezondheid op latere leeftijd. Er zijn steeds meer aanwijzingen dat vroege en permanente epigenetische veranderingen een belangrijke rol spelen in de onderliggende mechanismen. In dit artikel bespreken wij de rol van DNA-methylatie, het bekendste epigenetische mechanisme, op gezondheid en ziekte van kinderen. Wij gaan in op de achtergrond van DNA-methylatie, op factoren die hierop van invloed zijn en op gevolgen van DNA-methylatie. Onderzoek gericht op het identificeren van factoren tijdens en kort na de zwangerschap die via epigenetische mechanismen bijdragen aan de kans op ziekten, moet uiteindelijk leiden tot preventieprogramma’s gericht op de vroegste fase van het leven

    Trajectories and predictors of women's health-related quality of life during pregnancy

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    The objective of this study was to identify distinct trajectories and their predictors of healthrelated quali

    Associations of genetic risk scores based on adult adiposity pathways with childhood growth and adiposity measures

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    Background: Results from genome-wide association studies (GWAS) identified many loci and biological pathways that influence adult body mass index (BMI). We aimed to identify if biological pathways related to adult BMI also affect infant growth and childhood adiposity measures. Methods: We used data from a population-based prospective cohort study among 3,975 children with a mean age of 6 years. Genetic risk scores were constructed based on the 97 SNPs associated with adult BMI previously identified with GWAS and on 28 BMI related biological pathways based on subsets of these 97 SNPs. Outcomes were infant peak weight velocity, BMI at adiposity peak and age at adiposity peak, and childhood BMI, total fat mass percentage, android/gynoid fat ratio, and preperitoneal fat area. Analyses were performed using linear regression models. Results: A higher overall adult BMI risk score was associated with infant BMI at adiposity peak and childhood BMI, total fat mass, android/gynoid fat ratio, and preperitoneal fat area (all p-values < 0.05). Analyses focused on specific biological pathways showed that the membrane proteins genetic risk score was associated with infant peak weight velocity, and the genetic risk scores related to neuronal developmental processes, hypothalamic processes, cyclicAMP, WNT-signaling, membrane proteins, monogenic obesity and/or energy homeostasis, glucose homeostasis, cell cycle, and muscle biology pathways were associated with childhood adiposity measures (all p-values <0.05). None of the pathways were associated with childhood preperitoneal fat area. Conclusions: A genetic risk score based on 97 SNPs related to adult BMI was associated with peak weight velocity during infancy and general and abdominal fat measurements at the age of 6 years. Risk scores based on genetic variants linked to specific biological pathways, including central nervous system and hypothalamic processes, influence body fat development from early life onwards

    Bayesian imputation of time-varying covariates in linear mixed models

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    Studies involving large observational datasets commonly face the challenge of dealing with multiple missing values. The most popular approach to overcome this challenge, multiple imputation using chained equations, however, has been shown to be sub-optimal in complex settings, specifically in settings with longitudinal outcomes, which cannot be easily and adequately included in the imputation models. Bayesian methods avoid this difficulty by specification of a joint distribution and thus offer an alternative. A popular choice for that joint distribution is the multivariate normal distribution. In more complicated settings, as in our two motivating examples that involve time-varying covariates, additional issues require consideration: the endo- or exogeneity of the covariate and its functional relation with the outcome. In such situations, the implied assumptions of standard methods may be violated, resulting in bias. In this work, we extend and study a more flexible, Bayesian alternative to the multivariate normal approach, to better handle complex incomplete longitudinal data. We discuss and compare assumptions of the two Bayesian approaches about the endo- or exogeneity of the covariates and the functional form of the association with the outcome, and illustrate and evaluate consequences of violations of those assumptions using simulation studies and two real data examples

    Associations of maternal caffeine intake during pregnancy with abdominal and liver fat deposition in childhood

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    Background: Maternal caffeine intake during pregnancy is associated with an increased risk of childhood obesity. Studies in adults suggest that caffeine intake might also directly affect visceral and liver fat deposition, which are strong risk factors for cardio-metabolic disease. Objective: To assess the associations of maternal caffeine intake during pregnancy with childhood general, abdominal, and liver fat mass at 10 years of age. Methods: In a population-based cohort from early pregnancy onwards among 4770 mothers and children, we assessed maternal caffeine intake during pregnancy and childhood fat mass at age 10 years. Results: Compared with children whose mothers consumed <2 units of caffeine per day during pregnancy, those whose mothers consumed 4-5.9 and ≥6 units of caffeine per day had a higher body mass index, total body fat mass index, android/gynoid fat mass ratio, and abdominal subcutaneous and visceral fat mass indices. Children whose mothers consumed 4-5.9 units of caffeine per day had a higher liver fat fraction. The associations with abdominal visceral fat and liver fat persisted after taking childhood total body fat mass into account. Conclusions: High maternal caffeine intake during pregnancy was associated with higher childhood body mass index, total body fat, abdominal visceral fat, and liver fat. The associations with childhood abdominal visceral fat and liver fat fraction were independent of childhood total body fat. This suggests differential fat accumulation in these depots, which may increase susceptibility to cardio-metabolic disease in later life

    A common genetic variant at 15q25 modifies the associations of maternal smoking during pregnancy with fetal growth: The generation r study

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    Objective: Maternal smoking during pregnancy is associated with fetal growth retardation. We examined whether a common genetic variant at chromosome 15q25 (rs1051730), which is known to be involved in nicotine metabolism, modifies the associations of maternal smoking with fetal growth characteristics. Methods: This study was performed in 3,563 European mothers participating in a population-based prospective cohort study from early pregnancy onwards. Smoking was assessed by postal questionnaires and fetal growth characteristics were measured by ultrasound examinations in each trimester of pregnancy. Results: Among mothers who did not smoke during pregnancy (82.9%), maternal rs1051730 was not consistently associated with any fetal growth characteristic. Among mothers who continued smoking during pregnancy (17.1%), maternal rs1051730 was not associated with head circumference. The T-allele of maternal rs1051730 was associated with a smaller second and third trimester fetal femur length [differences -0.23 mm (95%CI -0.45 to -0.00) and -0.41 mm (95%CI -0.69 to -0.13), respectively] and a smaller birth length [difference -2.61 mm (95%CI -5.32 to 0.11)]. The maternal T-allele of rs1051730 was associated with a lower third trimester estimated fetal weight [difference -33 grams (95%CI -55 to -10)], and tended to be associated with birth weight [difference -38 grams (95%CI -89 to 13)]. This association persisted after adjustment for smoking quantity. Conclusions: Our results suggest that maternal rs1051730 genotype modifies the associations of maternal smoking during pregnancy with impaired fetal growth in length and weight. These results should be considered as hypothesis generating and indicate the need for large-scale genome wide association studies focusing on gene - fetal smoke exposure interactions
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